The cell surface peptidase, prostate-specific membrane antigen (PSMA) demonstrates intense overexpression in the majority of both primary and metastatic prostate cancers (PCa) and is expressed on the neovasculature of the majority of solid tumors including bladder, colon, liver, lung, renal, glioblastoma multiforme and melanoma (28). This along with a positive correlation of PSMA with traditional adverse prognostic factors aroused growing interest in evaluation of this target.1-3 Initially, antibodies (mAB) targeting PSMA have been used for PCa imaging and therapeutic approaches. The 111In labeled mAB capromab pendetide (ProstaScint, EUSA Pharma, Langhorne, Pa.) was approved in the USA in 1996. However, because the mAB, 7E11 targeted the intracellular domain of PSMA, its diagnostic value was rather limited.4 Another monoclonal PSMA antibody, J591 targets the extracellular domain of PSMA, but like most complete mABs it presents with a slow tumor accumulation and a long circulation time in blood. Thus, diagnostic mAB-tracers require prolonged imaging—even days after injection.5 Transferred to radionuclide therapy mABs commonly translate into an unfavorable dosimetry with pronounced hematotoxicity.6 Recently, the development of the Glu-urea-based high affinity small molecule PSMA inhibitors MIP1072 and MIP1095, either labeled with 123I for imaging or 131I for targeted radionuclide therapy, rendered rapid tumor uptake possible.7-9 Since PSMA is internalized through clathrin-coated pits27 either spontaneously or after binding of an antibody or an inhibitor, it is also an excellent target for endoradiotherapy. In this respect, the accumulation of the tracer in normal tissues has to be considered to prevent or diminish the extend of side effects, particularly in normal tissues that express low levels of PSMA including the proximal renal tubules of the kidney, salivary glands, and the brush-border epithelium of the small intestines.28 
In a positron emission tomography (PET)-based dosimetry study of 124I-MIP1095, doses of up to 300Gy in lymph node and bone metastases of castration refractory prostate cancer (CRPCa) were calculated. The organs with the highest off-target radiation doses were salivary glands (3.8 mSv/MBq), liver (1.7 mSv/MBq) and kidneys (1.4 mSv/MBq), while red marrow was 0.37 mSv/MBq.10 Therefore, kidneys may be the limiting factor for the maximum activity that can cumulatively be administered safely. However, improving kidney uptake without losing tumor dose is a real challenge because PSMA is physiologically expressed in the kidney tubules.1 The pharmacokinetics of MIP-1072 and MIP-1095 in animals have already been evaluated in detail.7 The authors reported a similar accumulation of both compounds in PSMA-expressing LNCaP xenografts but with very different pharmacokinetic profiles. MIP-1072 clears rapidly from target (tumor) and non-target (normal) tissues. In contrast, MIP-1095 presents a longer biological half-life in tumor but not in kidneys, which corresponds to a higher fraction of ligand induced receptor internalization and retention in tumor cells.
For the development of Glu-Urea based PSMA ligands, the structurally unrelated PSMA inhibitor 2-(phosphonomethyl)pentanedioic acid (PMPA) is commonly used as a competitor in blocking studies to demonstrate the specific binding of the molecule of interest, PSMA. In this respect simultaneous coinjection of 50 mg/kg PMPA resulted in a complete blocking of radiolabeled-MIP-1095 to binding sites in tumor and kidneys.7 The present disclosure describes a surprising discovery involving selective displacement by blocking agents of radionuclides from non-target, normal tissue and organs while retaining radionuclide at target, cancerous tissue sites through non-simultaneous administration methods.